With an increasing appreciation of the involvement of oxidation in the initial stages and progression of several major disease processes, particularly cardiovascular disease, the use of dietary antioxidants is being more critically evaluated. While not definitively proven at this time, the evidence accumulated to date is showing vitamin E to play a significant role in slowing or even reversing major disease processes. Investigators in this area are encouraged by the findings that the presumed mechanisms underlying the action of vitamin E are reasonably well understood as well as results of human studies in general, supporting predictions based on these presumed mechanisms. Equally encouraging to potential users of vitamin E is the extremely low toxicity. This article discusses the functions of vitamin E and the results of various studies that suggest its role in disease reduction, particularly cardiovascular diseases. Finally, some general guidelines for supplementation with vitamin E are presented.

VITAMIN E BASICS

The recognition of vitamin E's requirement in our diet goes back 75 years, when Evan and Bishop identified this substance as required for reproduction in the rat³. The name tocopherol was applied with tokos (for childbirth) and pherein (to bring forth) combined with ol (to denote its phenolic chemical nature). What is referred to as vitamin E is in reality a mixture of at least 8 related substances that can be divided into two groups, the tocopherols (alpha, beta, gamma, and delta forms) and the tocotrienols (alpha, beta, gamma, and delta forms)⁶. The two groups have different sources. The tocopherols are most plentiful in oil seeds, leaves, and other green parts of plants, while the tocotrienols are found mainly in the bran and germ portions of seeds and cereals. In humans, alpha-tocopherol appears to be the most important due to its high biological activity, or usability within the human body.

The major activity of vitamin E is the ability to function as an antioxidant, particularly for the preservation of polyunsaturated fats¹⁴; it is this group of fatty acids that is most susceptible to oxidative damage. In addition, there is an increasing recognition among cardiovascular disease investigators that lipid (fat) oxidation, especially the lipid contained in LDL (low density lipoprotein), accelerates the process of atherosclerosis¹³. Since vitamin E dissolves in fat, and is therefore said to be fat soluble, it is uniquely suited to functioning as an antioxidant in this environment. In addition, there is some evidence that other antioxidants may work with vitamin E to potentiate, or increase the effectiveness of, its antioxidant activity¹⁵.

VITAMIN E AND CARDIOVASCULAR DISEASE

Several lines of evidence have accumulated over the last two decades that suggest cholesterol levels are crucial for the progression of atherosclerosis⁹. Atherosclerosis is a disease process whereby cholesterol is deposited into the walls of blood vessels resulting in a gradual narrowing of the vessel along with reduced flexibility ("hardening of the arteries"). The reduction in the vessel's diameter not only reduces blood flow, but also makes a blood clot formation more common, and more likely to completely obstruct blood flow to downstream tissues. In the heart, where alternate blood flow is limited, this occurrence can precipitate a myocardial infarction ("heart attack").

LDL cholesterol (known as "bad" cholesterol), rather than total cholesterol appears to be the major source of cholesterol for starting this process. Experiments in animals have demonstrated that providing additional LDL to the blood accelerates this process¹³. Those same studies have shown that prior oxidation of LDL (which damages the LDL) increases the rate that cholesterol gets deposited in vessel walls. Studies in humans have also revealed that individuals can make antibodies against their own oxidized LDL and that levels of these antibodies correlate with risk for myocardial infarction¹⁰.

LDL is a tiny particle consisting of cholesterol, proteins, fatty acids, triglycerides, and an assortment of several types of antioxidants with alpha-tocopherol being dominant. Therefore, vitamin E is uniquely suited for the job of preventing LDL from becoming oxidized. To evaluate this possibility, various lines of investigations have been initiated to study this possibility¹⁵.

EPIDEMIOLOGICAL DATA

A number of studies have reported an inverse correlation between plasma concentrations of vitamin E and coronary mortality (death due to coronary artery disease), although this has not been consistently found. What these studies reveal is that the lowest risk for cardiovascular disease is found in those people with the highest levels of vitamin E in their blood The best studies to date have been prospective ones that have followed individuals who begin the study without cardiac disease and compared disease incidence with vitamin E intake. The Health Professionals Follow-up Study has followed nearly 40,000 men age 40 - 75 who started without cardiac disease¹¹. During the study period, the group with the highest intake of vitamin E had a 40% reduction in cardiovascular disease incidence compared to the lowest group. This risk reduction held up even after controlling for a wide array of other known risk factors. The study was also able to separate contributions from dietary sources and supplements. Only vitamin E supplements (>100 IU/day) had a significant effect.

The Nurses' Health Study followed over 87,000 women, age 34 - 59 for eight years and correlated vitamin E intake with cardiovascular disease incidence¹². A similar reduction in cardiac disease was noted at 34%. In addition, the investigators were able to show that only supplementation of greater than 100 IU/day of vitamin E was associated with the reduced risk. Another key finding was that at least 2 years of supplementation was necessary before risk reduction was found. This is particularly relevant because the proposed way that vitamin E works is by preventing LDL oxidation. Since the oxidized LDL deposit process is slow and gradual, occurring over many years, a reduction in oxidized LDL would be expected to only show up after some period of time of vitamin E use.

Finally, there have been studies assessing the progression of disease (which is different from disease induction, or cause). One such study was addressing atherosclerosis reversal by cholesterol lowering drugs with antioxidants⁵. In this case, supplementers who took >100 IU/day of vitamin E had less progression of their vessel narrowing compared to non-supplementers. In the group taking cholesterol lowering therapy and vitamin E, there was even partial regression (an improvement in the degree of narrowing) of the lesions. Other smaller trials have specifically examined vitamin E therapy in the case of angioplasty (surgery to repair obstructed blood vessels) to reduce restenosis (stenosis means obstruction to flow; restenosis is the process whereby the vessel becomes obstructed again in a rapid fashion after repair) rates². While the trends are in favor of vitamin E, these trials have been too small to detect statistically significant differences.

CO-ANTIOXIDANTS WORKING WITH VITAMIN E

The study of LDL oxidation has led investigators to examine the mechanism of how vitamin E protects polyunsaturated fats. Appreciation of other antioxidants has developed the notion that while vitamin E protects lipid, there must be other antioxidants present to recycle vitamin E. The other major antioxidants with substantial activity are coenzyme Q₁₀ and vitamin C¹⁵. The possibility of additional factors (these so called co-antioxidants) may provide an explanation for failing to detect a significant vitamin E effect in earlier studies where the additional antioxidants were not taken into account. This scenario has been evaluated in a study similar to the above designs, but utilizing an elderly population (ages 67 - 105) over a period of nine years⁷. In this group all the vitamin E users experienced a reduction in cardiac mortality (deaths due to cardiac disease) of 41%, but vitamin E use alone produced only a 31% reduction, whereas a combined vitamin E and C use produced a 48% reduction. This is strong evidence that antioxidants can work together to reduce risk of disease due to oxidative processes.

OTHER USES OF VITAMIN E

Certainly, cardiovascular diseases are by no means the sole province of vitamin E. The role of vitamin E in protecting the skin from UV (by the sun) damage is well appreciated. There are well established uses in specific pediatric diseases and at least one genetic disorder¹⁴. Improvement in immune system function is also plausible. There is some interest in possible cancer reduction (possibly related to immune system augmentation). One study has found a 23% reduction in cancer deaths, although the results were too weak to be considered conclusive evidence⁷.

SAFETY CONCERNS

A number of studies have addressed the safety of oral vitamin E supplementation^1,8. In some cases, doses were very high (2000 IU/day). In general, there have been little to no adverse effects reported. Most of the few side effects that appear in the literature are largely either anecdotal reports where vitamin E was presumed to be the cause or they are incidental findings in toxicity studies that have not been replicated by other studies. Also of comfort are animal studies where high doses have been used to look for mutagenic (the ability to damage DNA), carcinogenic (the ability to cause cancer), or teratogenic (the ability to cause birth defects when ingested by pregnant women) effects. None of these effects were found.

LIMITATIONS AND LACK OF PUBLIC POLICY RECOMMENDATIONS 

In spite of the above data, there has been no official declaration on the use of supplemental vitamin E. There are several reasons for this situation. In the first place, there are no prospective, randomized, double blind studies that have unequivocally demonstrated the ability of vitamin E for reducing cardiovascular disease. This type of study is regarded as the "gold standard", particularly for public policy. The only study that has come close is the infamous Finnish beta-carotene study which was looking at lung cancer⁴. Lost in the press reports were the facts that vitamin E was also included and that cardiovascular diseases were also evaluated. No effect of vitamin E was noted; however, this study actually validates earlier studies since only 50 IU/day of vitamin E was supplied and based on the previous studies, at least 100 IU/day are required for an effect.

From a safety standpoint, the doses needed to produce an apparent effect are well within tolerance limits, although a purist might wish to see more long term data. Lack of gold standard studies would appear to be one major reason for reluctance. Another aspect that may be troublesome for public policy officials is the need for supplementation, rather than mere dietary recommendations. The doses that appear beneficial are beyond the range that can be obtained from diet alone. This implies that people will need to buy supplements and this makes public policy officials more reluctant to offer this type of advice.

RECOMMENDATIONS

In order to achieve vitamin E levels commensurate with those that appear to afford some beneficial effects, supplementation is necessary; dietary sources of vitamin E are not sufficient to reach these amounts. At least 100 IU/day of vitamin should be taken; levels up to 400 IU/day are well within safety limits and are in the range of what many cardiologists are cautiously recommending now. In terms of what type of vitamin E to take, alpha-tocopherol is the most important form for LDL oxidation. On the other hand, excessive intake of one type may adversely affect other tocopherol species, so a mixed tocopherol is safer. There has been little or no examination of the tocotrienols, but their lower levels suggest that while they may possess some biological activity, the tocopherols are the important players. Since the preparations are standardized to IUs, there is less concern for the specific distribution provided that alpha-tocopherol is the major species. Natural and synthetic tocopherols have the same antioxidation properties, but the biological properties of the different forms vary, so natural is likely better.

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2. DeMaio SJ, King SB, Lembo NJ: Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). J Am Coll Nutr 11:68­73, 1992

3. Evans HM, Bishop KS: On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science 56:650­651, 1922

4. Heinonen OP, Albanes D, The Alpha­Tocopherol BC: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330:1029­1035, 1994

5. Hodis HN, Mack WJ, LaBree L, et al: Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 273:1849­1854, 1995

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7. Losonczy KG, Harris TB, Havlik RJ: Vitamin E and vitamin C supplement use and risk of all­cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 64:190­196, 1996

8. Meydani SN, Meydani M, Rall LC, et al: Assessment of the safety of high­dose, short­term supplementation with vitamin E in healthy older adults. Am J Clin Nutr 60:704­709, 1994

9. Mitchinson MJ: The new face of atherosclerosis. Br J Clin Prac 48:149­151, 1994

10. Puurunen M, Manttari M, Manninen V, et al: Antibody against oxidized low­density lipoprotein predicting myocardial infarction. Arch Int Med 154:2605­2609, 1994

11. Rimm EB, Stampfer MJ, Ascherio A, et al: Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 328:1450­1456, 1993

12. Stampfer MJ, Hennekens CH, Manson JE, et al: Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 328:1444­1449, 1993

13. Steinberg D, Parthasarathy S, Carew TE, et al: Beyond cholesterol. Modifications of low­density lipoprotein that increase its atherogenicity. N Engl J Med 320:915­924, 1989

14. Thakur ML, Srivastava US: Vitamin­E metabolism and its application. Nutr Res 16:1767­1809, 1996

15. Thomas SR, Neuzil J, Mohr D, et al: Coantioxidants make alpha­tocopherol an efficient antioxidant for low­density lipoprotein. Am J Clin Nutr 62:1357S­1364S, 1995